Centro de Biología Molecular "Severo Ochoa" (UAM-CSIC), Nicolás Cabrera, 1. Cantoblanco 28049 Madrid, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Valderrebollo, 5, 28031 Madrid, Spain.
Oxid Med Cell Longev. 2017;2017:9302761. doi: 10.1155/2017/9302761. Epub 2017 Oct 19.
Sporadic Alzheimer's disease corresponds to 95% of cases whose origin is multifactorial and elusive. Mitochondrial dysfunction is a major feature of Alzheimer's pathology, which might be one of the early events that trigger downstream principal events. Here, we show that multiple genes that control mitochondrial homeostasis, including fission and fusion, are downregulated in Alzheimer's patients. Additionally, we demonstrate that some of these dysregulations, such as diminished DLP1 levels and its mitochondrial localization, as well as reduced STOML2 and MFN2 fusion protein levels, take place in fibroblasts from sporadic Alzheimer's disease patients. The analysis of mitochondrial network disruption using CCCP indicates that the patients' fibroblasts exhibit slower dynamics and mitochondrial membrane potential recovery. These defects lead to strong accumulation of aged mitochondria in Alzheimer's fibroblasts. Accordingly, the analysis of autophagy and mitophagy involved genes in the patients demonstrates a downregulation indicating that the recycling mechanism of these aged mitochondria might be impaired. Our data reinforce the idea that mitochondrial dysfunction is one of the key early events of the disease intimately related with aging.
散发性阿尔茨海默病占 95%的病例，其起源是多因素的且难以捉摸的。线粒体功能障碍是阿尔茨海默病病理的一个主要特征，它可能是引发下游主要事件的早期事件之一。在这里，我们表明，控制线粒体动态平衡的多个基因，包括分裂和融合，在阿尔茨海默病患者中下调。此外，我们证明了这些失调中的一些，例如 DLP1 水平及其线粒体定位的降低，以及 STOML2 和 MFN2 融合蛋白水平的降低，发生在散发性阿尔茨海默病患者的成纤维细胞中。使用 CCCP 分析线粒体网络中断表明，患者的成纤维细胞表现出较慢的动力学和线粒体膜电位恢复。这些缺陷导致阿尔茨海默病成纤维细胞中衰老线粒体的大量积累。因此，对涉及患者自噬和线粒体自噬的基因的分析表明，下调表明这些衰老线粒体的回收机制可能受损。我们的数据强化了线粒体功能障碍是与衰老密切相关的疾病的关键早期事件之一的观点。
